rs587776441

Variant names:

• chrM-1644-G-A
• rs587776441
• unassigned_transcript_4786:c.43G>A

Your query was ambiguous. Multiple possible variants found:

• chrM-1644-G-A
• chrM-1644-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS4_Moderate PS3_Supporting PM5_Supporting PP1 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.1644G>A variant in MT-TV was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID:32906214). This variant has been reported in 7 individuals with primary mitochondrial disease with variable features including cardiac (hypertrophic cardiomyopathy, LBBB); neurologic (neurodegeneration/dementia, stroke-like episodes, recurrent encephalopathy, epilepsy, ataxia, dystonia, Parkinsonism, mood disorder/disturbances, fatigue, muscle weakness, exercise intolerance, neuropathy, cognitive impairment, developmental regression); audiologic (bilateral sensorineural hearing loss); renal (cystic renal disease); GI (severe GI dysmotility, cachexia); and endocrine (diabetes) concerns as well as lab abnormalities (elevated blood and CSF lactate, elevated CK), and brain imaging abnormalities (atrophy, basal ganglia lesions, MRS lactate peak); with heteroplasmy levels in multiple tissues ranging from 85% to homoplasmy (PS4; PMIDs: 15320572, 23847141, 18314141, 21986556, 24691472). This variant heteroplasmy level segregated with severity in 2 family members from 1 family (PP1; PMID:15320572). This variant is located at the same position as another variant associated with mitochondrial disease, m.1644G>T (PM5_supporting). This variant is absent in the GenBank data set and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA, as does HmtVar with a score of 1 (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID:24691472). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PS3_supporting, PM2_supporting, PM5_supporting, PP1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA913163370/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNV unassigned_transcript_4786 missense
• Scores: Mitotip Uncertain 13
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 O:1 Leigh-Syndrome-/-HCM-/-MELAS,Adult-Leigh-Syndrome
• Conservation: PhyloP100: 0.980
• Publications: 0 publications found

Genes affected

TRNV (HGNC:7500): (mitochondrially encoded tRNA valine)

MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR1 (HGNC:7470): (mitochondrially encoded 12S RNA) Enables DNA binding activity and DNA-binding transcription factor binding activity. Involved in several processes, including osteoblast proliferation; regulation of carbohydrate utilization; and regulation of phosphate metabolic process. Located in extracellular space; mitochondrion; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387342.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TV	ENST00000387342.1	TSL:6	n.43G>A		non_coding_transcript_exon	Exon 1 of 1
	MT-RNR2	ENST00000387347.2	TSL:6	n.-27G>A		upstream_gene	N/A
	MT-RNR1	ENST00000389680.2	TSL:6	n.*43G>A		downstream_gene	N/A

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56431

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56431

Mitomap

Disease(s): Leigh-Syndrome-/-HCM-/-MELAS,Adult-Leigh-Syndrome

Status: Cfrm-[LP],Reported

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	MELAS syndrome (3)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	13
Hmtvar	Pathogenic	1.0
PhyloP100		0.98

Other links and lift over

dbSNP: rs587776441; hg19: chrM-1646;